Public health officials in Hawaii have identified the first cluster of gonorrhea cases with reduced susceptibility to both drugs in the current recommended regimen, according to a report at the 2016 STD Prevention Conference taking place this week in Atlanta. While all 7 patients were successfully treated, this cluster underscores the need for new therapies, one of which was presented at the conference.

"There are new troubling signs that our current gonorrhea treatment may be losing its effectiveness," Jonathan Mermin, director of CDC’s National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, said at a September 21 media briefing. "Today's treatment may soon be in jeopardy. We urgently need more treatment options in the pipeline."

Gonorrhea is among the most common sexually transmitted infections (STIs), with more than 350,000 cases reported in the U.S. in 2014 -- although experts estimate that more than half of people are unaware they are infected and the actual number is closer to 800,000. Early gonorrhea is often asymptomatic, but if left untreated it can cause pelvic inflammatory disease, inflammation of the prostate, infertility, and ectopic pregnancy, as well as increasing the risk of acquiring and transmitting HIV.

Antibiotic resistance is a growing threat worldwide. This week the United National General Assembly took up the issue, with member countries committing to improve surveillance, diagnosis, and treatment. Resistant gonorrhea is among the biggest concerns, as Neisseria gonorrhoeae bacteria have already developed resistance to most of the drugs once used to treat it.

In August the World Health Organization (WHO) released new treatment guidelines for gonorrhea, chlamydia, and syphilis, noting that on a global level antibiotic resistance has increased rapidly and reduced treatment options. Multidrug-resistant strains of gonorrhea that do not respond to any available antibiotics have already been detected in some regions. WHO no longer recommends quinolone antibiotics because quinolone-resistant gonorrhea has emerged all over the world, making cephalosporins such as ceftriaxone and cefixime the mainstay of treatment.

To counter resistance, the U.S. Centers for Disease Control and Prevention (CDC) has repeatedly revised its gonorrhea treatment guidelines to phase out antibiotics that have become less effective. Currently there is just one recommended dual regimen consisting of an injection of ceftriaxone plus a single oral dose of azithromycin.

Resistant Cluster in Hawaii

Alan Katz from the University of Hawaii described findings from a joint investigation by the Hawaii State Department of Public Health and the CDC.

The Gonococcal Isolate Surveillance Project (GISP) collects N gonorrhoeaespecimens each month from the first 25 men with urethritis attending sexually transmitted disease clinics in about 30 cities. Hawaii carries out more extensive culture-based testing. Hawaii's location between the mainland U.S. and Asia, where resistant gonorrhea strains are expected to originate, makes it an important sentinel site for resistance trends.

"Hawaii is on the front line for antibiotic-resistant gonorrhea -- we’ve been one of the first states to see declining effectiveness of each drug over the years," said Katz. "That’s made us extremely vigilant, so we were able to catch this cluster early and treat everyone found who was linked to the cluster."

In the July 15 Morbidity and Mortality Weekly Report Surveillance Summary, CDC researchers reported that of the more than 5000 N gonorrhoeaeisolates collected in 2014, 2.5% showed reduced susceptibility to azithromycin, up from 0.6% in 2013. Decreased susceptibility to ceftriaxone or cefixime rose to 0.8% in 2014 from 0.4% in 2013 (though it had been as high as 1.4% in 2010 and 2011). In addition, 25.3% of isolates were resistant to tetracycline, 19.2% to ciprofloxacin, and 16.2% to penicillin.

However, no previous clusters of azithromycin-resistant gonorrhea that also showed reduced susceptibility to ceftriaxone or cefixime have been reported in the U.S. prior to the Hawaiian cases described this week.

Surveillance in Honolulu during April and May of 2016 identified 8 N gonorrhoeae isolates from 7 patients (1 person had both urethral and urine specimens) that showed very high-level resistance to azithromycin, and 5 had reduced susceptibility to ceftriaxone as well.

None of these patients had reported recent travel. All reported only heterosexual sex and were not having sex with each other. However, their N gonorrhoeae isolates were related, suggesting they perhaps had a common origin, Katz said.

Gail Bolan, director of CDC’s Division of STD Prevention, added that while we usually see decreased susceptibility coming from the west and among men who have sex with men, the Hawaii cluster has too few cases to say anything about trends by sexual orientation.

Decreased susceptibility -- indicated by an increase in a drug's minimum inhibitory concentration (MIC), or the lowest level that prevents bacterial growth -- is a warning sign that bacteria are evolving towards resistance. But the Hawaiian gonorrhea cases could still be successfully treated. All 7 patients were cured using the CDC's recommended dual regimen at standard doses (1 person started on another regimen but switched once resistance results were available). So far no confirmed treatment failures using this regimen have been reported in the U.S.

"Using both drugs ensures patients are cured of infection and prevents further transmission, but to preserve this option, providers should treat infections right away with the combination of azithromycin and ceftriaxone," Bolan stressed. "All health care providers should also promptly report any suspected treatment failure to local health officials and CDC to ensure rapid response to cases or clusters of concern."

New Therapy Looks Promising

Also at this week's STD conference, Stephanie Taylor from Louisiana State University reported promising results from a Phase 2 trial of ETX0914, a new topoisomerase inhibitor drug that works by a different mechanism than existing gonorrhea therapies.

This open-label trial included 179 participants (167 men and 12 women) with uncomplicated gonorrhea. They were randomly assigned to receive ETX0914 alone (either 2 or 3 grams) or ceftriaxone alone.

All patients in the 3g ETX0914 arm (47 of 47) and all but 1 in the 2g arm (48 or 49, or 98%) were cured. About 12% of participants reported adverse events, mostly mild. The most common were gastrointestinal side effects.

"EXT0914 was safe and effective in treating uncomplicated urogenital gonorrhea," Taylor said at the media briefing. "We look forward to this drug moving on to further clinical trials and we welcome a possible addition to our armamentarium to fight gonorrhea."

EXT0914 is being developed by Entasis Therapeutics; it was previously owned by AstraZeneca and known as AZD0914. Taylor said Phase 3 trials are not yet scheduled.

Public Health Response

CDC officials stressed that in addition to development of new therapies, fighting resistant gonorrhea will also require more widespread routine screening -- since may people do not have symptoms that would prompt them to get tested -- improved diagnostics, enhanced epidemiological surveillance systems, and rapid response capability.

"Increased gonorrhea screening is absolutely essential, as most people do not realize they have it," Bolan advised clinicians. "It is critical to follow CDC's treatment recommendations and be on high alert for treatment failure." She said there is currently not enough evidence to warrant changing CDC's recommended regimens or dosing.

Bolan added that when providers do not treat gonorrhea using the recommended regimen, people often feel better but the organism is still present in the body. Patients can't rely on symptoms and need to come back and get retested after finishing treatment to make sure they are cured.